More skeptisicm of the amyloid hypothesis

In Beating the Dementia Monster, we expressed some skepticism about the amyloid hypothesis and the current ideas about the role beta amyloids play in Alzheimer's disease.  The concept is that malformed proteins (actually, peptides) are excreted from the cells and form plaques in the brain.  The plaques stick to brain cells and kill them.  So the driving idea in research and the search for effective treatments was to find ways of removing the plaques and cure, or at least impede the disease.

This hasn't worked out very well.  I was skeptical of the hypothesis, although I toned down my approach following comments by reviewers of the manuscript prior to publication.  Researchers have found they can remove the plaques without curing the disease.  So this hasn't worked out very well.  Aduhelm removes the plaques, but no one is satisfied with how well it alters the course of the disease.  Lecanemab may be a little better, but it's not a cure.  And it might have killed some of the test subjects.  If repeated failures of experimental treatments wasn't enough, we found that fraud had reinforced faith in the amyloid hypothesis.  

In Beating the Dementia Monster, we discussed several alternatives to the amyloid hypothesis.  These included the propagation of gum disease bacteria into the brain as well as infection with the herpes virus.  Environmental considerations, such as air pollution, correlate with increased incidence of the disease.

Science is coming to terms with the fact that this is an extremely complex disease, and there may be far more moving parts than have been anticipated.

I read this fascinating but long article that traces the history of Alzheimer's research up to the present conundrum.  It's main focus is on the amyloid hypothesis and how it may have led researchers astray for many years.  Research was so focused on it as the explanation for Alzheimer's disease, that researchers pursuing other paths were marginalized.  Research money was scarce for anything outside of the amyloid bubble.

The author of the article is a bit biased, and she follows the story of a few iconoclast researchers.  In so doing, she focuses on one particular alternate explanation, the "endosomal-lysosomal hypothesis."  

One appeal of the amyloid hypothesis was that it was simple.  These plaques are forming and killing cells, so just get rid of them.  What could be easier.  Except that it hasn't been working out.

The endosomal-lysosomal hypothesis is a lot more complicated.  It involves autophagy, or how cells reach the end of their lives and recycle their constituent parts.  Aficionados of the Keto diet and the more extreme forms of intermittent fasting will know about promoting autophagy and its benefits. 

One distinction between the two hypotheses is the role of beta amyloid.  In the original amyloid hypothesis, amyloid is excreted from the cell, forms plaques, and the plaques kill cells from outside.  In the endosomal-lysosomal hypothesis, the amyloids kill the cells before they leave.  So cleaning out the amyloid from the brain is like removing the gravestones from the graveyard.  It doesn't make the people come back to life.  

The endosomal-lysosomal hypothesis posits that there is a complex disruption in how the cells die and recycle their constituents.  It's too complicated for this blog, but you can read the article.  And the author says something that I've been hearing for a while.  None of these hypotheses fully explains this incredibly complex disease.  Perhaps they are all playing different roles in a bigger story.  The author subtly recalls the Hindu parable of the blind men and the elephant.